The present invention is directed to novel taxanes which have utility as antileukemia and antitumor agents.
The taxane family of terpenes, of which taxol is a member, has attracted considerable interest in both the biological and chemical arts. Taxol is a promising cancer chemotherapeutic agent with a broad spectrum of antileukemic and tumor-inhibiting activity. Taxol has a 2xe2x80x2R, 3xe2x80x2S configuration and the following structural formula: 
wherein Ac is acetyl. Because of this promising activity, taxol is currently undergoing clinical trials in both France and the United States.
Cohn et al. reported in U.S. Pat. No. 4,814,470 that taxol derivatives having structural formula (2) below, have an activity significantly greater than that of taxol (1). 
Rxe2x80x2 represents hydrogen or acetyl and one of Rxe2x80x3 and Rxe2x80x2xe2x80x3 represents hydroxy and the other represents tert-butoxy-carbonylamino and their stereoisomeric forms, and mixtures thereof. The compound of formula (2) in which Rxe2x80x2 is hydrogen, Rxe2x80x3 is hydroxy, Rxe2x80x2xe2x80x3 is tert-butoxycarbonylamino having the 2xe2x80x2R, 3xe2x80x2S configuration is commonly referred to as taxotere.
Although taxol and taxotere are promising chemotherapeutic agents, they are not universally effective. Accordingly, a need remains for additional chemotherapeutic agents.
Among the objects of the present invention, therefore, is the provision of novel taxane derivatives which are valuable antileukemia and antitumor agents.
Briefly, therefore, the present invention is directed to C2 taxane derivatives. In a preferred embodiment, the taxane derivative has a tricyclic or tetracyclic core and corresponds to the formula: 
wherein
X1 is xe2x80x94OX6, xe2x80x94SX7, or xe2x80x94NX8X9;
X2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X3 and X4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X5 is xe2x80x94COX10, xe2x80x94COOX10, xe2x80x94COSX10, xe2x80x94CONX8X10, or xe2x80x94SO2X11;
X6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy protecting group, or a functional group which increases the water solubility of the taxane derivative;
X7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl;
X9 is an amino protecting group;
X10 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl;
X11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, xe2x80x94OX10, or xe2x80x94NX8X14;
X14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together with R14 forms a carbonate;
R2 is xe2x80x94OCOR31;
R2a is hydrogen;
R4 is hydrogen, together with R4a forms an oxo, oxirane or methylene, or together with R5a and the carbon atoms to which they are attached form an oxetane ring;
R4a is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano, hydroxy, xe2x80x94OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo,
R5a is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R5 forms an oxo, or together with R4 and the carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R6a forms an oxo;
R6a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R6 forms an oxo;
R7 is hydrogen or together with R7a forms an oxo,
R7a is hydrogen, halogen, protected hydroxy, xe2x80x94OR28, or together with R7 forms an oxo;
R9 is hydrogen or together with R9a forms an oxo;
R9a is hydrogen, hydroxy, protected hydroxy, acyloxy, or together with R9 forms an oxo;
R10 is hydrogen or together with R10a forms an oxo,
R10a is hydrogen, xe2x80x94OCOR29, hydroxy, or protected hydroxy, or together with R10 forms an oxo;
R14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
R28 is hydrogen, acyl, hydroxy protecting group or a functional group which increases the solubility of the taxane derivative;
R29 and R30 are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl, and
R31 is substituted phenyl.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
As used herein xe2x80x9cArxe2x80x9d means aryl; xe2x80x9cPhxe2x80x9d means phenyl; xe2x80x9cAcxe2x80x9d means acetyl; xe2x80x9cEtxe2x80x9d means ethyl; xe2x80x9cRxe2x80x9d means alkyl unless otherwise defined; xe2x80x9cBuxe2x80x9d means butyl; xe2x80x9cPrxe2x80x9d means propyl; xe2x80x9cTESxe2x80x9d means triethylsilyl; xe2x80x9cTMSxe2x80x9d means trimethylsilyl; xe2x80x9cTPAPxe2x80x9d means tetrapropylammonium perruthenate; xe2x80x9cDMAPxe2x80x9d means p-dimethylamino pyridine; xe2x80x9cDMFxe2x80x9d means dimethylformamide; xe2x80x9cLDAxe2x80x9d means lithium diisopropylamide; xe2x80x9cLHMDSxe2x80x9d means lithium hexamethyldisilazide; xe2x80x9cLAHxe2x80x9d means lithium aluminum hydride; xe2x80x9cRed-Alxe2x80x9d means sodium bis(2-methoxyethoxy) aluminum hydride; xe2x80x9cAIBNxe2x80x9d means azo-(bis)-isobutyronitrile; xe2x80x9c10-DABxe2x80x9d means 10-desacetylbaccatin III; FAR means 2-chloro-1,1,2-trifluorotriethylamine; protected hydroxy means xe2x80x94OR wherein R is a hydroxy protecting group; sulfhydryl protecting groupxe2x80x9d includes, but is not limited to, hemithioacetals such as 1-ethoxyethyl and methoxymethyl, thioesters, or thiocarbonates; xe2x80x9camine protecting groupxe2x80x9d includes, but is not limited to, carbamates, for example, 2,2,2-trichloroethylcarbamate or tertbutylcarbamate; and xe2x80x9chydroxy protecting groupxe2x80x9d includes, but is not limited to, ethers such as methyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl, methoxymethyl, 2-methoxypropyl, methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, dimethylarylsilyl ether, triisopropylsilyl ether and t-butyldimethylsilyl ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; and carbonates including but not limited to alkyl carbonates having from one to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl; isobutyl, and n-pentyl; alkyl carbonates having from one to six carbon atoms and substituted with one or more halogen atoms such as 2,2,2-trichloroethoxymethyl and 2,2,2-trichloro-ethyl; alkenyl carbonates having from two to six carbon atoms such as vinyl and allyl; cycloalkyl carbonates having from three to six carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phenyl or benzyl carbonates optionally substituted on the ring with one or more C1-6 alkoxy, or nitro. Other hydroxyl, sulfhydryl and amine protecting groups may be found in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by T. W. Greene, John Wiley and Sons, 1981.
The alkyl groups described herein, either alone or with the various substituents defined herein are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be substituted, straight, branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl and the like.
The alkenyl groups described herein, either alone or with the various substituents defined herein are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be substituted, straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
The alkynyl groups described herein, either alone or with the various substituents defined herein are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be substituted, straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.
The aryl moieties described herein, either alone or with various substituents, contain from 6 to 15 carbon atoms and include phenyl. Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Phenyl is the more preferred aryl.
The heteroaryl moieties described herein, either alone or with various substituents, contain from 5 to 15 atoms and include, furyl, thienyl, pyridyl and the like. Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, and amido.
The acyloxy groups described herein contain alkyl, alkenyl, alkynyl, aryl or heteroaryl groups.
The substituents of the substituted alkyl, alkenyl, alkynyl, aryl, and heteroaryl groups and moieties described herein, may be alkyl, alkenyl, alkynyl, aryl, heteroaryl and/or may contain nitrogen, oxygen, sulfur, halogens and include, for example, lower alkoxy such as methoxy, ethoxy, butoxy, halogen such as chloro or fluoro, nitro, amino, and keto.
In accordance with the present invention, it has been discovered that compounds corresponding to structural formula 3 show remarkable properties, in vitro, and are valuable antileukemia and antitumor agents. Their biological activity has been determined in vitro, using tubulin assays according to the method of Parness et al., J. Cell Biology, 91: 479-487 (1981) and human cancer cell lines, and is comparable to that exhibited by taxol and taxotere.
In a preferred embodiment of the present invention, the taxane has a structure corresponding to taxol or taxotere except for the C2 substituent, R2, which is xe2x80x94OCOR31 wherein R31 is selected from the group comprising 
and Z is alkyl, hydroxy, alkoxy, halogen, or trifluoromethyl. That is, R14 and R14a are hydrogen, R10 is hydrogen, R10a is hydroxy or acetoxy, R9 and R9a together form an oxo, R7 is hydrogen, R7a is hydroxy, R5 is hydrogen, R5a and R4 and the carbons to which they are attached form an oxetane ring, R4a is acetoxy, R1 is hydroxy, X1 is xe2x80x94OH, X2 is hydrogen, X3 is phenyl, X4 is hydrogen, X5 is xe2x80x94COX10, and X10 is phenyl or t-butoxy and the taxane has the 2xe2x80x2R, 3xe2x80x2S configuration.
In other embodiments of the present invention, the taxane has a structure which differs from that of taxol or taxotere with respect to the C2 substituent and at least one other substituent. For example, R9a may be hydrogen, R9 may be hydrogen, hydroxy, acetoxy or other acyloxy, R7 may be acetoxy or other acyloxy or halogen, R10a and R10 may each be hydrogen or together form an oxo; X3 may be selected from isobutenyl, isopropyl, cyclopropyl, n-butyl, t-butyl, cyclobutyl, cyclohexyl, furyl, thienyl, pyridyl or the substituted derivatives thereof, X5 may be xe2x80x94COX10 or xe2x80x94COOX10 and X10 may be selected from furyl, thienyl, pyridyl, alkyl substituted furyl or thienyl, tert-, iso- or n-butyl, ethyl, iso- or n-propyl, cyclopropyl, cyclohexyl, allyl, crotyl, 1,3-diethoxy-2-propyl, 2-methoxyethyl, amyl, neopentyl, PhCH2Oxe2x80x94, xe2x80x94NPh2, xe2x80x94NHnPr, xe2x80x94NHPh, and xe2x80x94NHEt.
Taxanes having the general formula 3 may be obtained by reacting a xcex2-lactam with alkoxides having the taxane tricyclic or tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a xcex2-amido ester substituent at C-13. The xcex2-lactams have the following structural formula: 
wherein X1-X5 are as defined above.
The xcex2-lactams can be prepared from readily available materials, as is illustrated in schemes A and B below: 
reagents: (a) triethylamine, CH2Cl2, 25xc2x0 C., 18 h; (b) 4 equiv ceric ammonium nitrate, CH3CN, xe2x88x9210xc2x0 C., 10 min; (c) KOH, THF, H2O, 0xc2x0 C., 30 min. or pyrolidine, pyridine, 25xc2x0 C., 3 h, (d) TESCl, pyridine, 25xc2x0 C., 30 min or 2-methoxypropene toluene sulfonic acid (cat.), THF, 0xc2x0 C., 2 h; (e) n-butyllithium, THF, xe2x88x9278xc2x0 C., 30 min; and an acyl chloride or chloroformate (X5xe2x95x90xe2x80x94COX10), sulfonyl chloride (X5xe2x95x90xe2x80x94COSX10) or isocyanate (X5xe2x95x90xe2x80x94CONX8X10); (f) lithium diisopropyl amide, THF xe2x88x9278xc2x0 C. to xe2x88x9250xc2x0 C.; (g) lithium hexamethyldisilazide, THF xe2x88x9278xc2x0 C. to 0xc2x0 C.; (h) THF, xe2x88x9278xc2x0 C. to 25xc2x0 C., 12 h.
The starting materials are readily available. In scheme A, xcex1-acetoxy acetyl chloride is prepared from glycolic acid, and, in the presence of a tertiary amine, it cyclocondenses with imines prepared from aldehydes and p-methoxyaniline to give 1-p-methoxyphenyl-3-acyloxy-4-arylazetidin-2-ones. The p-methoxyphenyl group can be readily removed through oxidation with ceric ammonium nitrate, and the acyloxy group can be hydrolyzed under standard conditions familiar to those experienced in the art to provide 3-hydroxy-4-arylazetidin-2-ones. In Scheme B, ethyl-xcex1-triethylsilyloxyacetate is readily prepared from glycolic acid.
In Schemes A and B, X1 is preferably xe2x80x94OX6 and X6 is a hydroxy protecting group. Protecting groups such as 2-methoxypropyl (xe2x80x9cMOPxe2x80x9d), 1-ethoxyethyl (xe2x80x9cEExe2x80x9d) are preferred, but a variety of other standard protecting groups such as the triethylsilyl group or other trialkyl (or aryl) silyl groups may be used. As noted above, additional hydroxy protecting groups and the synthesis thereof may be found in xe2x80x9cProtective groups in Organic Synthesisxe2x80x9d by T. W. Greene, John Wiley and Sons, 1981.
The racemic xcex2-lactams may be resolved into the pure enantiomers prior to protection by recrystallization of the corresponding 2-methoxy-2-(trifluoromethyl) phenylacetic esters. However, the reaction described hereinbelow in which the xcex2-amido ester side chain is attached has the advantage of being highly diastereoselective, thus permitting the use of a racemic mixture of side chain precursor.
The alkoxides having the tricyclic or tetracyclic taxane nucleus and a C-13 metallic oxide or ammonium oxide substituent have the following structural formula: 
wherein R1-R14a are as previously defined and M comprises ammonium or is a metal optionally selected from the group comprising Group IA, Group IIA and transition metals, and preferably, Li, Mg, Na, K or Ti. Most preferably, the alkoxide has the tetracyclic taxane nucleus and corresponds to the structural formula: 
wherein M, R2, R4a, R7, R7a, R9, R9a, R10, and R10a are as previously defined.
The alkoxides can be prepared by reacting an alcohol having the taxane nucleus and a C-13 hydroxyl group with an organometallic compound in a suitable solvent. Most preferably, the alcohol is a protected baccatin III, in particular, 7-O-triethylsilyl baccatin III (which can be obtained as described by Greene, et al. in JACS 110: 5917 (1988) or by other routes) or 7,10-bis-O-triethylsilyl baccatin III.
As reported in Greene et al., 10-deacetyl baccatin III is converted to 7-O-triethylsilyl-10-deacetyl baccatin III according to the following reaction scheme: 
Under what is reported to be carefully optimized conditions, 10-deacetyl baccatin III is reacted with 20 equivalents of (C2H5)3SiCl at 23xc2x0 C. under an argon atmosphere for 20 hours in the presence of 50 ml of pyridine/mmol of 10-deacetyl baccatin III to provide 7-triethylsilyl-10-deacetyl baccatin III (4a) as a reaction product in 84-86% yield after purification. The reaction product may then optionally be acetylated with 5 equivalents of CH3COCl and 25 mL of pyridine/mmol of 4a at 0xc2x0 C. under an argon atmosphere for 48 hours to provide 86% yield of 7-O-triethylsilyl baccatin III (4b). Greene, et al. in JACS 110, 5917 at 5918 (1988).
The 7-protected baccatin III (4b) is reacted with an organometallic compound such as LHMDS in a solvent such as tetrahydrofuran (THF), to form the metal alkoxide 13-O-lithium-7-O-triethylsilyl baccatin III as shown in the following reaction scheme: 
As shown in the following reaction scheme, 13-O-lithium-7-O-triethylsilyl baccatin III reacts with a xcex2-lactam in which X1 is preferably xe2x80x94OX6, (X6 being a hydroxy protecting group) and X2-X5 are as previously defined to provide an intermediate in which the C-7 and C-2xe2x80x2 hydroxyl groups are protected. The protecting groups are then hydrolyzed under mild conditions so as not to disturb the ester linkage or the taxane substituents. 
Both the conversion of the alcohol to the alkoxide and the ultimate synthesis of the taxane derivative can take place in the same reaction vessel. Preferably, the xcex2-lactam is added to the reaction vessel after formation therein of the alkoxide.
Compounds of formula 3 of the instant invention are useful for inhibiting tumor growth in animals including humans and are preferably administered in the form of a pharmaceutical composition comprising an effective antitumor amount of compound of the instant invention in combination with a pharmaceutically acceptable carrier or diluent.
Antitumor compositions herein may be made up in any suitable form appropriate for desired use; e.g., oral, parenteral or topical administration. Examples of parenteral administration are intramuscular, intravenous, intraperitoneal, rectal and subcutaneous administration.
The diluent or carrier ingredients should not be such as to diminish the therapeutic effects of the antitumor compounds.
Suitable dosage forms for oral use include tablets, dispersible powders, granules, capsules, suspensions, syrups, and elixirs. Inert diluents and carriers for tablets include, for example, calcium carbonate, sodium carbonate, lactose and talc. Tablets may also contain granulating and disintegrating agents such as starch and alginic acid, binding agents such as starch, gelatin and acacia, and lubricating agents such as magnesium stearate, stearic acid and talc. Tablets may be uncoated or may be coated by unknown techniques; e.g., to delay disintegration and absorption. Inert diluents and carriers which may be used in capsules include, for example, calcium carbonate, calcium phosphate and kaolin. Suspensions, syrups and elixirs may contain conventional excipients, for example, methyl cellulose, tragacanth, sodium alginate; wetting agents, such as lecithin and polyoxyethylene stearate; and preservatives, e.g., ethyl-p-hydroxybenzoate.
Dosage forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions and the like. They may also be manufactured in the form of sterile solid compositions which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain suspending or dispersing agents known in the art.
The water solubility of compounds of formula (3) may be improved by modification of the C2xe2x80x2 and/or C7 substituents. For instance, water solubility may be increased if X1 is xe2x80x94OX6 and R7a is xe2x80x94OR28, and X6 and R28 are independently hydrogen or xe2x80x94COGCOR1 wherein
G is ethylene, propylene, xe2x80x94CHxe2x95x90CHxe2x80x94, 1,2-cyclohexane, or 1,2-phenylene,
R1=OH base, NR2R3, OR3, SR3, OCH2CONR4R5, OH
R2=hydrogen, methyl
R3=(CH2)nNR6R7; (CH2)nN⊕R6R7R8Xxe2x8ax96
n=1 to 3
R4=hydrogen, lower alkyl containing 1 to 4 carbons
R5=hydrogen, lower alkyl containing 1 to 4 carbons, benzyl, hydroxyethyl, CH2CO2H, dimethylaminoethyl
R6R7=lower alkyl containing 1 or 2 carbons, benzyl or R6 and
R7 together with the nitrogen atom of NR6R7 form the following rings 
R1=lower alkyl containing 1 or 2 carbons, benzyl
Xxe2x8ax96=halide
base=NH3, (HOC2H4)3N, N(CH3)3, CH3N(C2H4OH)2, NH2(CH2)6NH2, N-methylglucamine, NaOH, KOH.
The preparation of compounds in which X1 or X2 is xe2x80x94COGCOR1 is set forth in Haugwitz U.S. Pat. No. 4,942,184 which is incorporated herein by reference.
Alternatively, solubility may be increased when X1 is xe2x80x94OX6 and X6 is a radical having the formula xe2x80x94COCXxe2x95x90CHX or xe2x80x94COXxe2x80x94CHXxe2x80x94CHXxe2x80x94SO2Oxe2x80x94M wherein X is hydrogen, alkyl or aryl and M is hydrogen, alkaline metal or an ammonio group as described in Kingston et al., U.S. Pat. No. 5,059,699 (incorporated herein by reference).
Taxanes having alternative C9 substituents may be prepared by selectively reducing the C9 keto substituent to yield the corresponding C9 xcex2-hydroxy derivative. The reducing agent is preferably a borohydride and, most preferably, tetrabutylammoniumboro-hydride (Bu4NBH4) or triacetoxyborohydride.
As illustrated in Reaction Scheme 1, the reaction of baccatin III with Bu4NBH4 in methylene chloride yields 9-desoxo-9xcex2-hydroxybaccatin III 5. After the C7 hydroxy group is protected with the triethylsilyl protecting group, for example, a suitable side chain may be attached to 7-protected-9xcex2-hydroxy derivative 6 as elsewhere described herein. Removal of the remaining protecting groups thus yields 9xcex2-hydroxy-desoxo taxol or other 9xcex2-hydroxytetracylic taxane having a C13 side chain. 
Alternatively, the C13 hydroxy group of 7-protected-9xcex2-hydroxy derivative 6 may be protected with trimethylsilyl or other protecting group which can be selectively removed relative to the C7 hydroxy protecting group as illustrated in Reaction Scheme 2, to enable further selective manipulation of the various substituents of the taxane. For example, reaction of 7,13-protected-9xcex2-hydroxy derivative 7 with KH causes the acetate group to migrate from C10 to C9 and the hydroxy group to migrate from C9 to C10, thereby yielding 10-desacetyl derivative 8. Protection of the C10 hydroxy group of 10-desacetyl derivative 8 with triethylsilyl yields derivative 9. Selective removal of the C13 hydroxy protecting group from derivative 9 yields derivative 10 to which a suitable side chain may be attached as described above. 
As shown in Reaction Scheme 3, 10-oxo derivative 11 can be provided by oxidation of 10-desacetyl derivative 8. Thereafter, the C13 hydroxy protecting group can be selectively removed followed by attachment of a side chain as described above to yield 9-acetoxy-10-oxo-taxol or other 9-acetoxy-10-oxotetracylic taxanes having a C13 side chain. Alternatively, the C9 acetate group can be selectively removed by reduction of 10-oxo derivative 11 with a reducing agent such as samarium diiodide to yield 9-desoxo-10-oxo derivative 12 from which the C13 hydroxy protecting group can be selectively removed followed by attachment of a side chain as described above to yield 9-desoxo-10-oxo-taxol or other 9-desoxo-10-oxotetracylic taxanes having a C13 side chain. 
Reaction Scheme 4 illustrates a reaction in which 10-DAB is reduced to yield pentaol 13. The C7 and C10 hydroxyl groups of pentaol 13 can then be selectively protected with the triethylsilyl or another protecting group to produce triol 14 to which a C13 side chain can be attached as described above or, alternatively, after further modification of the tetracylic substituents. 
Taxanes having C9 and/or C10 acyloxy substituents other than acetate can be prepared using 10-DAB as a starting material as illustrated in Reaction Scheme 5. Reaction of 10-DAB with triethylsilyl chloride in pyridine yields 7-protected 10-DAB 15. The C10 hydroxy substituent of 7-protected 10-DAB 15 may then be readily acylated with any standard acylating agent to yield derivative 16 having a new C10 acyloxy substituent. Selective reduction of the C9 keto substituent of derivative 16 yields 9xcex2-hydroxy derivative 17 to which a C13 side chain may be attached. Alternatively, the C10 and C9 groups can be caused to migrate as set forth in Reaction Scheme 2, above. 
Taxanes having alternative C2 and/or C4 esters can be prepared using baccatin III and 10-DAB as starting materials. The C2 and/or C4 esters of baccatin III and 10-DAB can be selectively reduced to the corresponding alcohol(s) using reducing agents such as LAH or Red-Al, and new esters can thereafter be substituted using standard acylating agents such as anhydrides and acid chlorides in combination with an amine such as pyridine, triethylamine, DMAP, or diisopropyl ethyl amine. Alternatively, the C2 and/or C4 alcohols may be converted to new C2 and/or C4 esters through formation of the corresponding alkoxide by treatment of the alcohol with a suitable base such as LDA followed by an acylating agent such as an acid chloride.
Baccatin III and 10-DAB analogs having different substituents at C2 and/or C4 can be prepared as set forth in Reaction Schemes 6-10. To simplify the description, 10-DAB is used as the starting material. It should be understood, however, that baccatin III derivatives or analogs may be produced using the same series of reactions (except for the protection of the C10 hydroxy group) by simply replacing 10-DAB with baccatin III as the starting material. Derivatives of the baccatin III and 10-DAB analogs having different substituents at C2 and at least one other position, for instance C1, C4, C7, C9, C10 and C13, can then be prepared by carrying out any of the other reactions described herein and any others which are within the level of skill in the art.
In Reaction Scheme 6, protected 10-DAB 3 is converted to the triol 18 with lithium aluminum hydride. Triol 18 is then converted to the corresponding C4 ester using Cl2CO in pyridine followed by a nucleophilic agent (e.g., Grignard reagents or alkyllithium reagents). 
Deprotonation of triol 18 with LDA followed by introduction of an acid chloride selectively gives the C4 ester. For example, when acetyl chloride was used, triol 18 was converted to 1,2 diol 4 as set forth in Reaction Scheme 7.
Triol 18 can also readily be converted to the 1,2 carbonate 19. Acetylation of carbonate 19 under vigorous standard conditions provides carbonate 21 as described in Reaction Scheme 8; addition of alkyllithiums or Grignard reagents to carbonate 19 provides the C2 ester having a free hydroxyl group at C4 as set forth in Reaction Scheme 6. 
As set forth in Reaction Scheme 9, other C4 substituents can be provided by reacting carbonate 19 with an acid chloride and a tertiary amine to yield carbonate 22 which is then reacted with alkyllithiums or Grignard reagents to provide 10-DAB derivatives having new substituents at C2. 
Alternatively, baccatin III may be used as a starting material and reacted as shown in Reaction Scheme 10. After being protected at C7 and C13, baccatin III is reduced with LAH to produce 1,2,4,10 tetraol 24. Tetraol 24 is converted to carbonate 25 using Cl2CO and pyridine, and carbonate 25 is acylated at C10 with an acid chloride and pyridine to produce carbonate 26 (as shown) or with acetic anhydride and pyridine (not shown). Acetylation of carbonate 26 under vigorous standard conditions provides carbonate 27 which is then reacted with alkyl lithiums to provide the baccatin III derivatives having new substituents at C2 and C10. 
10-desacetoxy derivatives of baccatin III and 10-desoxy derivatives of 10-DAB may be prepared by reacting baccatin III or 10-DAB (or their derivatives) with samarium diiodide. Reaction between the tetracyclic taxane having a C10 leaving group and samarium diiodide may be carried out at 0xc2x0 C. in a solvent such as tetrahydrofuran. Advantageously, the samarium diiodide selectively abstracts the C10 leaving group; C13 side chains and other substituents on the tetracyclic nucleus remain undisturbed. Thereafter, the C9 keto substituent may be reduced to provide the corresponding 9-desoxo-9xcex2-hydroxy-10-desacetyoxy or 10-desoxy derivatives as otherwise described herein.
C7 dihydro and other C7 substituted taxanes can be prepared as set forth in Reaction Schemes 11, 12 and 12a. 
As shown in Reaction Scheme 12, Baccatin III may be converted into 7-fluoro baccatin III by treatment with FAR at room temperature in THF solution. Other baccatin derivatives with a free C7 hydroxyl group behave similarly. Alternatively, 7-chloro baccatin III can be prepared by treatment of baccatin III with methane sulfonyl chloride and triethylamine in methylene chloride solution containing an excess of triethylamine hydrochloride.
Taxanes having C7 acyloxy substituents can be prepared as set forth in Reaction Scheme 12a, 7,13-protected 10-oxo-derivative 11 is converted to its corresponding C13 alkoxide by selectively removing the C13 protecting group and replacing it with a metal such as lithium. The alkoxide is then reacted with a xcex2-lactam or other side chain precursor. Subsequent hydrolysis of the C7 protecting groups causes a migration of the C7 hydroxy substituent to C10, migration of the C10 oxo substituent to C9, and migration of the C9 acyloxy substituent to C7.
A wide variety of tricyclic taxanes are naturally occurring, and through manipulations analogous to those described herein, an appropriate side chain can be attached to the C13 oxygen of these substances. Alternatively, as shown in Reaction Scheme 13, 7-O-triethylsilyl baccatin III can be converted to a tricyclic taxane through the action of trimethyloxonium tetrafluoroborate in methylene chloride solution. The product diol then reacts with lead tetraacetate to provide the corresponding C4 ketone. 
Recently a hydroxylated taxane (14-hydroxy-10-deacetylbaccatin III) has been discovered in an extract of yew needles (CandEN, p 36-37, Apr. 12, 1993). Derivatives of this hydroxylated taxane having the various C2, C4, etc. functional groups described above may also be prepared by using this hydroxylated taxane. In addition, the C14 hydroxy group together with the C1 hydroxy group of 10-DAB can be converted to a 1,2-carbonate as described in CandEN or it may be converted to a variety of esters or other functional groups as otherwise described herein in connection with the C2, C4, C7, C9, C10 and C13 substituents.
The following examples are provided to more fully illustrate the invention.